Are you sure your patient has a non-bacterial osteitis syndrome? What are the typical findings for this disease?

CRMO and SAPHO represent the spectrum of autoinflammatory bone disease in which non-infectious osteitis is the unifying feature collectively termed non-bacterial osteitis (NBO). The systemic autoinflammatory diseases include NBO and the periodic fever syndromes. All are considered defects of innate immunity characterized by recurrent attacks of spontaneous inflammation in the absence of autoimmunity or infection.

The most common clinical findings in the NBO syndromes (including CRMO and SAPHO) include recurrent episodes of bone pain with or without fever due to discrete inflammatory lesions in one or more bones of the axial or peripheral skeleton. X-rays and magnetic resonance imaging (MRIs) of affected areas show irregular radiolucent foci with sclerosis in different stages of healing. Bone scans show uptake of Technetium-99 in active lesions. The bone lesions are indistinguishable from infectious osteomyelitis on imaging. Bone biopsy histology shows nonspecific inflammation with neutrophilic infiltrate early and mixed inflammatory cells, sclerosis and new bone formation in older lesions. Cultures of bone aspirates or biopsies are sterile. The boney lesions are refractory to antimicrobial therapy.

Other associated findings in the NBO syndromes frequently include comorbid autoinflammatory or autoimmune diseases commonly involving the skin, bowel, and/or joints. The diseases generally follow an unpredictable disease course with periodic waxing and waning of symptoms over a few years to up to 10 years.

NBO is a diagnosis of exclusion. As such it is critical to rule out infection, malignancy, or systemic autoimmune disorders other than arthritis or inflammatory bowel disease to make a diagnosis of NBO. Skin and bone biopsies, particularly if only a single osteolytic focus is present, should be used to exclude other causes and confirm diagnosis of NBO. (See Table I)

Table I.

Proposed criteria for diagnosis of non-bacterial osteitis

Suspect diagnosis if ≥2 majorOR1 major and ≥3 minor criteria are present:

CRMO

There is a striking overlap of symptoms and comorbidities between CRMO and SAPHO. CRMO may represent the pediatric presentation of SAPHO.

The classic clinical presentation of CRMO is episodic bone pain with low grade fever. The bone pain is usually has an insidious onset, is well localized, and aching in character. Patients may be afebrile. On exam there is tenderness to palpation, with swelling and warmth overlying the involved bone. Objective signs of arthritis may involve one or more joints. The skin findings include psoriasis, palmoplantar pustulosis and cystic acne with scarring. The disease course will be characterized by frequent exacerbations and remissions. The average age of onset is 10 years, with a range of 4-55 years. The mean time from onset of symptoms to diagnosis is18 months.

Bone involvement in CRMO is characterized by an average of 2-18 bone lesions, usually in an asymmetric distribution, and often localized to bone sites typically seen in acute hematogenous (infectious) osteomyelitis in children. 10% of patients have a unifocal lesion, requiring bone biopsy for definitive diagnosis to rule out infectious osteomyelitis.

On laboratory testing, mild or moderate elevations of ESR (15-65 mm/h) and CRP (5-40 mg/l) are found during flares in 60% patients. White blood cell counts are normal or only mildly elevated (5-15,000 x 109/l). RF is negative and ANA is also usually negative unless the patient has concomitant autoimmune thyroiditis. 10% of patients are positive for HLA-B27.

Comorbid conditions found in CRMO include other autoinflammatory or autoimmune disorders involving skin, joints or bowel:

The wide range in frequency of the associated diseases is probably due to discordance in the timing of the NBO and the onset of skin, bone and bowel manifestations, and confusion resulting from the clinical overlap between CRMO and SAPHO.

40-50% of 1st or 2nd degree relatives have chronic autoimmune or autoinflammatory disease.

SAPHO

As noted above there is significant overlap in clinical symptoms, laboratory findings and comorbidities between SAPHO and CRMO.

Features that distinguish SAPHO from CRMO are the finding of skin manifestations in more than 85% of patients, an older age at presentation, and predilection for different bones.

The classic presentation of SAPHO is with bone pain due to chronic recurrent osteitis and concomitant severe skin disease without fever. The most common site of involvement in SAPHO (unlike CRMO) is anterior chest wall pain (see below). Bone involvement usually includes 1-8 bone lesions in asymmetric distribution. Tenderness to palpation, swelling and warmth overlying involved bone is noted on exam. The osteitis is unifocal in 40-50% patients, and often requires diagnostic bone biopsy to rule out infection.

Severe scarring acne, psoriasis or palmoplantar pustulosis is commonly present on examination. SAPHO may present as acute or chronic arthritis with skin manifestations, especially psoriasis. The average age of onset is 30 years with a range of 12-65 years.

The most common sites of skeletal osteolytic foci are:

- Anterior chest wall/sternocostoclavicular joint: 60%

- Spine: 35%

- Long bones: 25%

- Clavicle: 20-25%

- Knee/ankle/wrist: 11%

- Sacroiliac joint: 6%

Laboratory findings include mildly elevated ESR (10-65 mm/h) and CRP (10-40 mg/l) during flares of osteitis and skin inflammation. The CBC shows either a normal or mildly elevated white blood cell count (5-15,000 x 109/l). RF and ANA are negative except when there is concomitant autoimmune thyroiditis. Four to 15% of patients are HLA-B27 positive.

Comorbid conditions include the onset of skin manifestation either with or even before the development of bone lesions in up to 85%. The typical skin finding is a neutrophilic dermatosis such as:

Palmoplantar pustulosis: 40-50%.

Acne conglobata or fulminans: >25%.

Psoriasis vulgaris: 20-55%.

30-35% of patients have two concomitant skin manifestations.

Sweet syndrome and pyoderma gangrenosum is less common.

Crohn's disease or ulcerative colitis in 10%, usually presents 0.5-5 yr after onset of bone pain.

Majeed Syndrome

Majeed Syndrome is an autosomal recessively inherited NBO with a more severe phenotype than either CRMO and SAPHO. The onset of symptoms is usually later in infancy or within the first 2 years of life. A predilection for small bone involvement, the fever pattern, the course of the disease and the association with a dyserythropoietic anemia, all help distinguish Majeed Syndrome from DIRA, CRMO and SAPHO.

Symptoms of Majeed Syndrome include the distinctive clinical course that includes flares of bone pain and fever >38.5°C for 3-4 days, recurring every 2-4 weeks. Severe joint and bone pain begins abruptly and there is tenderness to palpation with warmth and soft tissue swelling over involved bones and joints. Chronic multifocal osteomyelitis in the metaphyses of long bones and osteolytic foci in small joints of hands and feet are distinctive features. A dyserythropoietic anemia may develop in first year of life. Hepatomegaly and transient neonatal cholestatic jaundice occur in some patients.

DIRA

DIRA is an autosomal recessively inherited NBO due to deficiency of IL-1 receptor antagonist (IL-1Ra) that presents in the perinatal period. The very early age of onset, severity of disease, association with Sweet syndrome rather than other neutrophilic dermatoses, and unusual radiologic findings distinguish it from CRMO and SAPHO. The lack of anemia, an earlier presentation and unusual radiologic findings distinguish DIRA from Majeed syndrome.

Symptoms of DIRA usually appear in the first 2-3 weeks of life. The infants appear ill and exhibit signs of systemic inflammation without fever. The patients have irritability and pain on palpation of long bones, joint swelling and a pustular rash that can vary in appearance. Other clinical features include significant osteopenia with associated fractures, hepatosplenomegaly, CNS vasculopathy, venous thromboses, pneumonitis or pulmonary hemosiderosis resulting in respiratory distress, and oral mucosal lesions.

Bone involvement includes multifocal osteolytic lesions and periosteal elevation along the metaphysis of multiple long bones. Involvement of the spine and skull is also seen and may lead to vertebral collapse and secondary cervical spine fusion. Heterotopic ossification may occur around hip and proximal femur. Epiphyseal ballooning of anterior ribs occurs in nearly 100% infants.

Magnetic resonance imaging (MRI) with and without contrast of specific joints and bones for characterization of osteolytic lesion and differentiation from malignant or benign tumors, arthritis, other bony abnormalities.

Both may improve bone pain, but no data to support one option over another. Methotrexate is used for treatment of arthritis, IBD, and neutrophilic dermatoses versus sulfasalazine which is used to treat mild arthritis and IBD, not skin manifestations.

All TNF inhibitors improve bone pain, neutrophilic dermatoses and arthritis, but etanercept should not be used if IBD present since may trigger flare. Likely benefit for NBO: Infliximab ≥ adalimumab > etanercept, although risk of adverse reaction is inversely correlated with possible benefit.Choice of pamidronate versus TNF inhibitors in NBO patients refractory to NSAIDS, should be based at least in part on manifestations. TNF inhibitors decrease inflammation, associated pain, fever, acute phase reactants, as well as IBD, neutrophilic dermatoses and possibly early osteolytic lesions with predominantly neutrophilic infiltrates. Pamidronate may help bone pain as part of bone remodeling of chronic bone lesions and associated collapse.

Described in seven individuals from three consanguineous Arab families.

Unique mutation identified in each affected family.

Prevalence of mutation: 1:35,000 in Jordan.

DIRA

Incidence: extremely rare.

Described in nine patients from Newfoundland, the Netherlands, Lebanon, and Puerto Rico.

Apparent founder effect with mutation frequency of 0.4% in Newfoundland and 2.6% in Puerto Rico.

What’s known about the genetics?

CRMO

Etiology is currently unknown.

Mostly sporadic disease and likely multifactorial.

Studies of concordance in monozygotic twins and families with more than one affected sibling and normal parents suggest an autosomal recessive inheritance as well, although underlying gene defects have not been identified.

No association between NOD2/CARD15
mutations in Crohn's disease and CRMO.

Murine model of CRMO is due to a mutation in the pstpip2 gene and the human homolog, PSTPIP2, is structurally related to PSTPIP1
, mutations in which cause PAPA syndrome.

A recently identified susceptibility locus for NBO on chromosome 18q21.3-22 includes PSTPIP2.

SAPHO

Mostly sporadic and likely multifactorial similar to CRMO.

Recent analysis of 38 patients found no association with PSTPIP2
, NOD2 and LPIN2 genetic variants.

Majeed Syndrome

Due to homozygous mutations in the gene LPIN2 encoding the protein lipin-2, whose functions have not been fully elucidated.

Original descriptions identified three disease-causing mutations: S734L, C181X, and R776SfsX66.

DIRA

Due to homozygous mutations in the IL1RN gene that are unique to country of origin: N52KfsX25, E77X, Q54X.

Also results from a homozygous 175-kb deletion of the IL1RN
locus encoding the IL-1 receptor antagonist (IL-1Ra) and five IL-1 family members in one patient.

How do these pathogens/genes/exposures cause the disease?

CRMO

Unknown for sporadic form, but single gene defects encoding proteins critical to inflammation may contribute to pathogenesis.

One such protein, PSTPIP2, associates with actin and may play a role in inhibition of monocyte/macrophage function during inflammation.

Other clinical manifestations that might help with diagnosis and management

Management of NBO is geared towards control of comorbidities as well as bone inflammation.

Treatment regimens vary considerably for the spectrum of NBO as a result, interfering with assessments of efficacy.

What complications might you expect from the disease or treatment of the disease?

Disease complications include bone thinning and collapse, stress fractures, kyphoscoliosis, limitations in range of motion of affected joints, deformities, and decreased ability to do activities of daily living.

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